A well-known approach to stabilizing an aqueous suspension formulation of a drug, particularly a poorly soluble drug, is by the principle of controlled flocculation. According to such an approach, an aqueous medium or vehicle for the drug is provided that permits aggregation of particles of the drug to form a floc. A desirable floc is one that tends to settle but is readily resuspended with slight agitation and remains in uniform suspension during a period of time long enough to permit administration, for example parenterally, to a subject. Controlled flocculation of a poorly soluble drug generally requires presence in the aqueous medium of one or more wetting agents and one or more suspending agents.
U.S. Pat. No. 3,457,348 to Nash & Haeger, incorporated herein by reference, discloses that polyoxyethylene nonionic surfactants, for example polyoxyethylene sorbitan monooleate, are suitable wetting agents for this purpose. A formulation of sulfadiazine comprising polyoxyethylene sorbitan monooleate and polyethylene glycol (PEG) of molecular weight 4000 is specifically described therein.
Polysorbates such as polysorbate 80 (polyoxyethylene (20) sorbitan monooleate) and PEGs of molecular weight from about 1000 to about 20,000 such as PEG 3350 are known wetting and suspending agents for use in injectable aqueous injection formulations. For example, Depo-Provera® contraceptive injection of Pharmacia & Upjohn is an aqueous suspension formulation of the steroidal drug medroxyprogesterone acetate containing:
medroxyprogesterone acetate150mgPEG 335028.9mgpolysorbate 802.41mgsodium chloride8.68mgmethylparaben1.37mgpropylparaben0.15mgwater for injectionq.s. to 1mlSee Physicians' Desk Reference, 56th ed. (2002), pp. 2798-2801.
It has been found that where an aqueous suspension of a hydrophobic drug includes, for provision of stability through controlled flocculation, compounds such as polysorbates and/or PEGs having polyoxyethylene chains, the suspension tends to show a decline in such stability with time. This decline in stability can be manifested, for example, in thickening of the formulation and/or poor resuspendability of a solid deposit, and, especially in unbuffered or weakly buffered formulations, can be accompanied or mediated by a drift in pH with time, usually a downward drift. Excessive drift in pH of an injectable formulation is undesirable not only for its impact on physical stability of the formulation but also because of the risk of carrying the formulation outside a biocompatible pH range.
Polyoxyethylene chains are susceptible, in presence of oxygen over time, to oxidation of C—H groups to C—O—O—H (hydroperoxy) groups. This oxidative degradation process is known to occur, for example, in polysorbates. See Donbrow et al. (1978), J. Pharm. Sci. 67, 1676-1681. The hydroperoxy groups are susceptible to further degradation by a variety of mechanisms, leading to cleavage of the polyoxyethylene chains and, at least in some situations, formation of formic acid and/or other compounds as degradation products with a concomitant lowering of pH. Presence and quantitation of degradation products and/or measurement of pH can provide an indication of the degree of oxidative degradation, if any, that has occurred in a sample of a formulation.
Oxidative degradation can also affect formulation ingredients other than those comprising polyoxyethylene chains, with a variety of undesirable effects, including, in addition to decline in physical stability and pH drift, accumulation of degradation products that can be toxic or otherwise deleterious if administered by injection, and, where the ingredient subject to oxidative degradation is an active ingredient, loss of potency.
By reducing or minimizing exposure of the formulation to oxygen, problems of oxidative degradation can be substantially overcome. For example, if an injectable formulation is packaged in an airtight container such as a vial having little or no headspace acting as a reservoir of gaseous oxygen, i.e., if the container is substantially filled with the formulation, oxidative degradation is likely to be minimized. This can be an acceptable way to package a formulation that does not require agitation to homogenize the formulation prior to use, for example a formulation in the form of an aqueous solution. However, the lack of headspace becomes a serious problem in the case of an aqueous suspension formulation exhibiting controlled flocculation, because it greatly impedes ability to agitate the formulation, for example by shaking the container, to resuspend a settled floc and provide a fine homogeneous suspension for parenteral injection. Where the formulation is packaged in a unit-dose container such as a vial, it is particularly important to be able to resuspend substantially all of a drug deposit so that the full dose can be administered.
One approach to reducing exposure of an aqueous suspension formulation to oxygen yet providing a sufficient headspace for agitation is to provide an oxygen-depleted atmosphere in the headspace, for example an atmosphere enriched in nitrogen or a noble gas. This approach is not always convenient, and it can be difficult and expensive in practice to displace substantially all of the oxygen from headspace atmosphere.
It would be of benefit in the art to provide an alternative means of reducing exposure to oxygen of an injectable aqueous suspension formulation, that permits resuspension by agitation immediately prior to use.